Treatment of hair and scalp with compositions containing estriol

ABSTRACT

IMPROVEMENT OR ALLEVIATION OF CERTAIN UNDESIRABLE CONDITIONS OF THE SCALP, INCUDING CERTAIN TYPES OF NON-IRREVERSIBLE HAIRFALL USING ESTRIOL, AND COMPOSITIONS THEREOF PARTICULARLY USEFUL IN SUCH TREATMENT.

United States Patent 3,729,560 TREATMENT OF HAIR AND SCALP WITH COR[POSITIONS CONTAINING ESTRIOL Gosta Hagerman, Lund, Sweden, assignor toAktieholaget Leo (A/B Leo), Halsingborg, Sweden No Drawing. Filed Mar.25, 1969, Ser. No. 810,351 Claims priority, application Great Britain,Apr. 2, 1968, 15,852/ 68 Int. Cl. A61k 11/06 US. Cl. 424-238 9 ClaimsABSTRACT OF THE DISCLOSURE Improvement or alleviation of certainundesirable conditions of the scalp, including certain types ofnon-irreversible hairfall using estriol, and compositions thereofparticularly useful in such treatment.

BACKGROUND OF THE INVENTION In the past, many claims have been madeconcerning the successful treatment of baldness by means of variousdifferent topical preparations but, as far as is known to the presentapplicant, none of these has proved effective.

Such lack of success is to be expected, inasmuch as the common baldnessin men, also designated male pattern baldness or premature baldness, maybe considered primarily a physiological reaction in persons having aconstitutional, often inherited, tendency toward this type of baldness.The presence of a normal amount of the male sex hormone, testosterone,is the main eliciting factor in individual prone to the development ofsuch premature baldness, which may therefore also be designatedandrogenetic (meaning that it depends upon or is elicited by malefactors). It has long been known, that castration may stop the furtherprogress of this type of baldness, and that systemic treatment with themale sex hormone testosterone will again cause further hair loss in suchcases.

It is not claimed that this type of male pattern baldness orandrogenetic baldness, in which cases the hair follicles of the affectedareas have already adapted themselves to the production only of anunpigmented, almost invisible down of no cosmetic value, can be cured oreven improved or ameliorated by the treatment or compositions of thepresent invention, or that any hair growth whatever can be produced inan already bald area. In contrast, however, in male pattern orandrogenetic alopecia (thinning out of the hair), the process ofsuccessive degeneration of the hair follicles has only begun and shouldtherefore be reversible or at least delayable, if an adequate treatmentcan be found.

In addition, it is not presently possible to suggest that the treatmentor compositions of the invention be used in alopecia areata (reversiblehair loss leading to temporary baldness in rounded patches) anddefinitely no recommendation is made for use in alopecia totalis (totalbaldness of the scalp, sometimes also including eyebrows, eyehairs, andbody hairs). In such form, the background of the baldness is uncertainand topical treatment of the type discussed here is not of any provedvalue. However, as stated, the present invention is not concerned withtreatment of such conditions.

In addition, in those cases where hairfall is elicited by toxic ormetabolic influences such as febrile infections or anemia, or by somesort of mechanical traction, such circumstances must obviously beelucidated and removed, if haiifall from such causes is to beeliminated. Such treatment is accordingly no part of the presentinvention.

In addition, baldness in patches due to various condi tions leading toatrophy of the hair follicles is beyond the scope of any treatment orcompositions contemplated by the present invention.

Having now disclaimed any association with the quackery of the pastrelating to anti-baldness preparations, and having established certainareas in which the treatment and compositions of the present inventionare not applicable, the present applicant will now proceed to describethe areas in which his novel treatment and compositions are effective.

SUMMARY OF THE INVENTION The present invention relates to the employmentof the stated compound for the treatment of certain particularconditions of the scalp for the improvement or alleviation thereof. Theconditions which may be treated and thus improved or alleviated are inprinciple reversible types and accordingly subject to improvement. Theseinclude hairfall (efiluvium or defluvium), hair thinning (alopecia) andspecifically the male and female pattern types of hairfall or hairthinning (also designated alopecia androgenetica). In such conditions,the treatment and compositions of the invention have been shown toproduce a marked diminution in the rate of hairfall.

Employment of the particular compound constituting the active principleof the present invention, such substance having a demonstrable hormonaleffect (sexual and/or non specific) which is directed to the pertinenttarget organ (the scalp and its appendages), but at the same timeproducing a negligible effect on the internal or primary sex organs, isof the essence of the invention. Because of the fact that the compoundof the invention has such unique properties, it is possible to treat thetarget organ in question, namely, the scalp, topically with sufficientand extremely high concentrations of the hormone, actually relativelygreat quantities thereof, without the risk of unwanted systemic sideelfects upon resorption of the active material from the sites of topicalapplication.

The primary application of the active material is in the form ofsolutions or suspensions in a volatile solvent, usually in an alcoholicfluid vehicle, preferably in an aqueous alcoholic fluid vehicle, butother non-toxic pharmaceutically and topically acceptable organicsolvents may also be employed. Solvents comprising at least mainlyvolatile components are definitely preferred, such volatile componentsrepresenatively being a lower alcohol, e.g., ethyl or propyl alcohol,mixtures thereof, preferably together with some water, which is lessvolatile but still a slowly evaporating component, and the solvent mayalso contain minor amounts of other non-harmful solvents of lesser or novolatility. The active principle may, however, also be applied alone orin combination with other substances or in vehicles of other types,e.g., salves, ointments, or the like, for production of the desiredeffect, although other vehicles do not appear desirable for optimumresults and are cosmetically less acceptable.

As far as can be ascertained by the present applicant, the materialemployed as active ingredient in the method and compositions of thepresent invention has hitherto not been used or even suggested for thepurposes of the present invention. In brief, the findings upon which thepresent application is based are as follows:

After some months of topical treatment of the scalp with the activeingredient of the present invention, namely, estriol, in the form oflotions and solutions, preferably of a volatile, e.g., alcoholic,nature, the following effects can be obtained in a large percentage ofpatients treated, particularly females:

(A) A pathologically-increased hair shedding can be decreased even downto normal values, according to the impression of the patient, andaccording to hair samples collected over a lengthy time span.

(B) The status of the hair roots by microscopic evaluation in some casescan be shown to have improved as to the percentage of actively growing(anagen) roots in relation to dormant (telogen) roots in an extractedhair tuft.

In female patients especially, reports of their hair dresser and familyof a general impression of an improved general condition of the hair,sometimes to a considerable degree, is not uncommon.

FURTHER BACKGROUND OF THE INVENTION Estriol is a normally occurringestrogenic horomone in human beings, but it is not very activeestrogenically as shown by the most commonly used animal tests.Estradiol, the most studied human estrogen, has about three hundred tofive hundred times greater estrogenic effect than its metabolic endproduct, estriol, when studied by the commonly employed Allen-Doisy testwhich measures vaginal cornification in spayed mice or rats. Estriolalso has a very weak eifect on the endometrium (inner layer of theuterus). Therefore, until recently, this hormone has been consideredmainly as an unimportant by-product of estradiol metabolism. Neither hasestriol been suggested for treatment of the scalp or hair and certainlynot as an agent for topical application to the scalp for its effect uponhair follicles which exerts no disturbing systemic effects afterresorption from these application sites. A search of the literature hasfailed to reveal any attempt to employ the active ingredient of theinvention for treatment of hairfall, alopecia, or other conditions ofthe scalp or hair.

The finding of the present applicant that the active ingredient of theinvention exerts local action upon the scalp and hair but no measurablesystemic effect was unpredictable and contra-indicated by the results ofearlier workers. For example, topically applied ethynyl estradiol, anactive estrogen, was tested with negative results on the productivity ofthe androgen-sensitive sebaceous glands of the forehead, at which sitethe estrogen was directly applied. The authors point out that their ownstudies rule out the possibility that estrogens antagonize androgenswhen applied at the level (or site) of the target organ and that manystudies indicate that hormones with opposing actions on a specifictarget organ ordinarily do not exhibit competitive inhibition whenapplied at the site of the target organ (Strauss, Kligman and Pochi, I.Investig. Dermatology 39, 139l55 1962). Thus, such locally-directedactivity of the particular estrogen which is the active ingredient ofthe present invention and competitive inhibition of androgen at thetarget organ where applied is contraindicated by the results andstatements of these workers as late as 1962. In their opinion, theresults (as desired in this case) would have to depend on estrogensdepressing pituitary output of gonadotropin, which in turn would depressthe production of androgens from testicles and adrenals. Also, theestrogens might possibly depress androgen production by a direct efiecton the adrenals.

However, the present results contradict the conclusions of Strauss etal. as being much too generalized. Topical application of the activeingredient of this invention has definitely produced observable, evenmeasurable, effects on the hair, particularly in different types offemale pattern alopecia (hair thinning) and usually also a decrease inthe concomitant oiliness of the hair, and without undesirable sideeffects, as already noted.

Although not wishing in any way to be limited by theory, one possibleexplanation for the present results and their contradiction of prior artworkers may be that, although with men having a very strong trend to atleast partial baldness, estrogenic treatment by any route would havesmall chance of success, in men with a weaker trend to baldness, thatis, a less pronounced sensitivity to androgens in certain scalp areas, alocal alteration of the androgen-estrogen balance by topical applicationof the active ingredient of this invention might produce a delayingefiect in this particular target organ, namely, the hair follicles incertain sexually dependent scalp areas, even if the same 4 activeingredient might not alfect the sebaceous glands outside the scalp. y

In women with different types of female pattern alopecia (alopeciaandrogenetica), this sensitivity of haid follicles in certain scalpareas to androgen and the trend to a high degree of hair thinning isobviously much weaker, because of their inherent androgen-estrogenbalance, and in such cases topical treatment could conceivably producestill better chances of success.

These theoretical considerations, particularly the latter one, seem toagree well with the experience of the present applicant as to topicaltreatment with the active ingredient of the present invention,especially when administered in a volatile, e.g., dilute alcoholic,solvent.

Another factor and mechanism which, however, must also be considered inthis respect is the age-dependency of male pattern alopecia, whichfrequently increases with the age of the subject. Obviously, the earlierin their way to premature aging the hair follicles are when estrioltreatment is started, the greater chance of a successful delay in theaging (and alopecia-prone) process.

Whatever the reason or scientific explanation may be, topicalapplication of the active ingredient and compositions of the presentinvention has produced remarkably good elfects in female patients withdiffuse hairfall or thinning out of the female pattern alopecia type(alopecia androgenetica), including one or more of the following:Decrease in hair shedding, even down to normal values; obvious decreasein weight of hair samples collected regularly over a long period;improvement of hair roots by microscopic evaluation showing decrease ininactive telogen count to active anagen count in tufts of hair extractedduring successive visits; an improved general condition, texture, life,lustre, laying possibility and so on.

In men with male pattern alopecia, results have been much lessspectacular, but still sufficiently successful to warrant continuationof the treatment over a period of servial years.

As already noted, the various side effects which commonly appear inpatients treated with estrogens did not appear when using the activeingredient and compositions of the invention in the manner of thepresent invention. It thus appears that one can actually speak of aseparated hormonal activity in the sense that the active ingredient isactive at the site of topical application for purposes of the presentinvention, but produces, as far as has been observed to date, nosystemic effects on the internal sexual organs upon resorption.

Obviously, the treatment and compositions of the invention are moreeffective in the more diffuse type of alopecia in women know as femalepattern alopecia, also known as androgenetic alopecia, several variantsof which pattern are common. At any rate, the type of hairfall in bothmale and female patients which responds to and which can be expected toshow some response to a treatment can generally be called theandrogenetic type, as distinguished from other types previouslymentioned. It is of course only a non-irreversible type of hairfall thatcan be treated successfully according to the pres ent invention, sinceobviously no useful purpose is or can be served, except perhapsreduction of oily seborrhoea, by treating a man having a very stronghereditary trend to hairfall and consecutive patterned alopecia, andparticularly when this process has already progressed to actualbaldness. For this reason, the typical male pattern baldness, which canreally be considered as a secondary male sexual characteristicdeveloping in persons with a strong hereditary trend to abnormalsensitivity or reactivity of the hair follicles in certain areas of thescalp to androgen, particularly to testosterone, must be expected torespond much more slightly if at all to any treatment, and such is theobserved fact when employing the treatment and compositions of thepresent invention. Thus, only in men with a weaker trend to baldness canany observable reduction in hairfall and/or the resulting thinning outof the hair be expected. In women, where the trend toward baldnessbecause of the female hormone balance is much less, the observableeffect is much greater and occurs more frequently.

Just what mechanism is involved is still not free from doubt. Theactivity of estrogen in evoking a marked increase in the activity ofseveral amino acid-activating enzymes, which are involved in thebiosynthesis of protein, and thus also with hair growth phenomenon, maybe a factor. Considering the very high rate of mitotic (cell division)activity in the hair follicle (which delivers scalp hair at a rate of0.3+ mm. per day), a mechanism of this type may by itself be a possibleexplanation for the favorable clinical findings reported in the presentapplication. The exact mechanism or reason for the favorable effectsobserved is, however, not completely understood.

COMPOSITIONS The active ingredient of the invention, as previouslystated, is estriol. The compositions of the invention involve the activeingredient in a pharmaceutically and cosmetically acceptable solvent,which comprises at least mainly if not entirely volatile components,such as lower alcohols, preferably ethyl or isopropyl alcohol or amixture thereof, preferably diluted with water. In such composition, thewater is a less volatile, but still slowly evaporating component. Minoramounts of still less volatile or non-volatile solvents of an acceptablenature may be included.

Other solvents which may also be used, and combinations thereof, includeother lower alcohols, combinations thereof, acetone, combinations ofother solvents with lower alcohols such as acetone plus ethanol, othercombinations with methanol, ethanol, propanol or butanol; n-hexane,dioxane, propylene glycol, polyethylene glycol, vegetable oils, andsolutions or emulsions of the fore going with water. The presence ofsome water in the compositions of the invention is definitely preferred.A volatile solvent such as an alcohol, e.g., ethyl or isopropyl alcohol,or acetone is also greatly preferred. Nonvolatile or only slightlyvolatile components are always preferably present in only minorproportions.

The concentration of the active ingredient in the solution or suspensionshould be at least 0.02 percent, is preferably at least 0.05 percent,and has a maximum useful upper limit of approximately 0.2 percent.Higher percentages up to about 1 percent may be used if desired but arenot economically attractive. Striking results have been obtained atabout 0.1 percent or slightly above, but treatment effects can sometimesbe increased by increasing the concentration of the active ingredient inthe compositions of the invention.

METHOD OF TREATING The treatment of the invention is carried out byapplying the active ingredient in any acceptable form, advantageously ina pharmaceutically and cosmetically acceptable topical solvent, andpreferably in the form of a composition according to the presentinvention, to the scalp subject to the undesirable condition, preferablyonce a day. The recommended period of treatment is at least six monthsbefore a preliminary assessment of the results can be made. If noobvious hairfall is present, most male patients will require from eightto twelve months of treatment or even more before satisfactoryobservable results are obtained. The minimum period of treatment beforefavorable results have been positively effected has been approximatelytwelve weeks.

In any event, the recommended treatment is application to the parts ofthe hair and/or scalp having the undesirable condition, preferably atleast once daily, and the recommended period of treatment beforedefinite assessment of positive effect is at least six months. For

maximum efiicacy a year or more is usually recommended, particularly formen.

SPECIFIC DESCRIPTION OF THE INVENTION The following examples ofcompositions and procedure which may be employed according to thepresent invention, are given by way of illustration only and are not tobe construed as limiting.

Example 1 The composition most commonly used in the clinical experimentsreported herein is designated Composition 0L and has the followingformula:

Estriol 0.1 gram. Benzalkonium chloride (antibacterial surface-activeagent) 0.05 gram.

Ethyl alcohol 39.0 grams.

Corrigentia odor As desired.

Distilled water To make 100ml.

of solution.

Use of such a composition has been found entirely satisfactory. In manycases, application of approximately 50 ml. of the composition per weekhas been the prescribed regimen, the treatment period extending from aminimum of twelve to fifteen weeks to four years or even more. In somecases about 20 ml. of the composition is administered for at least about12 weeks or at least about 6 months.

Example 2 The following illustrates the preparation of a larger quantityof a composition according to the invention:

Ingredients: Grams Estriol 500 Benzalkonium chloride, 50% 500 Desirableodor 500 Ethyl alcohol, by volume 213,000 Water to 465,000

For a total of 500 liters. The specific gravity of the solution is 0.93.

The first three ingredients are dissolved in the ethyl alcohol by mixingand stirring. When all is dissolved, Water is added to make 465kilograms (500 liters).

The estriol is relatively difficult to dissolve in dilute ethanol.Therefore, it is preferred to add the water only after complete solutionof the estriol in the concentrated ethanol.

Variations: Estriol is practically insoluble in toluene and chloroform.In vegetable oils other than peanut oil and with adjuvants, forinstance, a few percent of benzyl alcohol, it is possible to obtain muchhigher amounts in solution. Other solvent possibilities are mentioned inthe foregoing.

At 10 C. the solubility of estriol in m1. of solvent is as follows: In95% ethanol 1.2%, acetone 0.27%, methanol 1.66%, butanol 0.57%, anddioxane 0.63%.

At 20 C. 0.006% in peanut oil, 0.8% in propylene glycol.

At 30 C. 1.65% in 95% ethanol, 0.41% in acetone, 2.02% in methanol,0.74% in butanol, and 0.97% in dioxane.

Other pharmaceutically and cosmetically acceptable disinfectants orpreservatives may be added as required and these are of course notcritical to the method or com positions of the invention. The exactperfume or aroma is of course a matter of choice.

All the foregoing compositions and combinations may be employedaccording to the invention, but the compositions having theaforementioned percentages of active ingredients, and those containingalcohol, especially together with some water, are by far preferred.

Background information on hair growth and hair root dynamics: The rootof a normal, growing scalp hair develops from the bottom of thecylindrical hair follicle,

which is molded on a vascular papilla (dermal papilla) originating inthe corium (deeper layer of skin) and capped by the hair bulb which is arounded downward extension of the hair root. This bulb represents thematrix of the hair, where the hair grows by means of a very intensivecell division (mitosis); The mass of new cells moves upwards along thefollicular channel towards the scalp, and during this movement the cellsundergo alterations in form and composition, particularly thekeratinization process (transformation into horny substance), whichleads to the formation of the emerging hair shaft. The growing, healthyhair matrix, producing approximately 0.35 mm. of hair daily, is a tissueof very high metabolic and mitotic (cell division) activity, andtherefore particularly sensitive to different toxic and otherinterferences.

After a certain period of active growth, the hair root will begin toregress and loses it supply of nutrition from the papillary vessels. Itthen transforms into a resting hair, which during a period of 3-4 monthsslides slowly along the follicular channel towards the scalp surfaceuntil it is shed spontaneously or after slight pulling. The dead(resting) hair is in itself not sensitive to toxic or otherinterferences, but is easier to epilate (i.e., pull out) than thegrowing hair.

Each hair follicle thus undergoes recurring cycles of active growth,regression and rest. In man, follicular activity is not synchronized andneighboring follicles are normally at different stages of the cycle.

The main stages of the hair cycle are known as anagen, the phase ofactive growth; catagen, the phase of regression; and telogen, theresting period. This sequence is invariable and irreversible; oncecatagen is induced, spontaneously or pathologically, telogen inevitablyfollows and is succeeded by a new anagen hair growing up from a reformedpapilla and matrix. In the young adult human scalp the average durationof anagen is about three years (one to six years); catagen occupies twoweeks or less, and telogen three to four months. At any given moment,85-95% of scalp follicles are in anagen, 414% in telogen (i.e., thetelogen count or percentage is 4-14), and 1% or less in catagen. If oneaccepts 100,000 as a rough estimate of the follicle population of thescalp, the daily moult will be in the region of 20-75 hairs.

Connection between hairfall (elfluvium) and telogen count: (See Kligman,Archives of Dermatology 83, 175-198, 1961.) Very strong, toxicinfluences, particularly treatment with high doses of a cancerchemotherapeutic drug (which acts by means of inhibiting cell divisionor mitosis), will damage the multiplicating cells of the matrix soheavily, that the hair will break off in the follicle and fall out inthe anagen phase. This anagen effiuviurn already begins one or two weeksafter the administration of the drug.

Most other types of ha-irfall, partically those in which the damagingfactor does not set in very suddenly and at the same time is not toostrong, are of the telogen eflluvium type. This entails a shortening ofthe anagen period by prematurely inducing a transformation to oatagen,followed in a few weeks by further transformation to the telogen phase.The telogen count will now be much increased. The time, from the actualdamage in the matrix until most of the resulting premature telogen hairsare shed, will be about 2-4 months. This long latent period between theinsult and the visible shedding is obligatory for telogen hairfall andtelogen alopecia (telogen thinning of the hair). As patients are notaware of this long latent period, the primary condition if any will notbe disclosed spontaneously and only if a correct history is taken.

If the cause of telogen eifiuvium is a brief period of disease, toxic ordyshormonal influences, etc., the follicles will usually revert to theirnormal, long anagen phase, the telogen count decreases, the hairfallstops and the new-growing hairs will be restored to their earlier stateand life span.

If the damaging influence is of a more continuous type, e.g., along-lasting general disease or hormonal imbalance, the shortened anagenphase may occur also in the following batches of hair in the pertinentarea, which will therefore retain an increased telogen count. Little bylittle, the follicles will grow narrower and shorter, deliveringsuccessively finer, less pigmented hairs with decreasing life span.These will transform into telogen and then fall out already when havingattained a length of only a few centimeters. The affected region willnow, usually, have a very high telogen count and a decreased averagehair shaft diameter. In many cases, particularly in the so-called malepattern alopecia, a partial or total transformation to thin, short,unpigmented vellus hairs (downy hairs) will result, making the affectedareas appear more or less bald.

If an effective treatment can be given, it will, obviously, have tocontinue for several months, before the poorly functioning follicleswill be restored to a degree, where thicker hairs with a close-to-normallife span can again be produced, and the telogen count (if increased)can reverse towards normal values. Therefore, when the possible efiicacyof a new treatment is studied, no definite evaluation can be undertakenuntil the lapse of a considerable time span.

This theoretical consideration tallies well with the experience of thepresent applicant. Even patients who ultimately obtained an obviousimprovement could sometimes see little effect in the first three or fourmonths. Actually, the telogen count may show a reverse towards normalitybefore the patient has observed an evident improvement. Obviously,results after trial periods of say two or three months should not becounted when patient material is totally evaluated.

As the telogen count may vary between about 4 to 15 or even 20 percentbetween normal individuals (and also considerably between differentareas of the same scalp), one single telogen count is often notsufiicient to indicate either diagnosis or condition of the scalp. If,on the other hand, a relatively high telogen count de creasessuccessively during a long course of treatment, this will be oneindication of treatment efficacy. It should be pointed out here, that ahigh pretreatment count might well decrease markedly after the firstperiod of successful treatment, to increase somewhat during furthertreatment, owing to the scalp having adapted its hair change dynamics tothe new metabolic balance ultimately produced by the continuoustreatment.

Preparation used and treatment routine: A solution of composition 0Lcontaining estriol, 0.1% in 39% (weight) ethyl alcohol, also containing0.05% of benzalkonium chloride and a small amount of perfume, was usedduring the investigation. The preparation is distributed in 200 ml.sprinkler-topped bottles, intended for use over a four-week period andcarrying on one side a graduation for four weekly rations.

The patients are instructed to apply the preparation to the thinningparts of the scalp once daily, using each weeks ration in the intendedtime. Some of these bottles are given to the patient at consultation,but during continued treatment they are usually sent to the patientdirectly. The number of bottles delivered to each patient is recorded tocontrol the pursuit of the treatment and the actual consumption of thepreparation.

Summary of clinical results: Upon a recent survey of the clinicalmaterial, 122. patients had been treated and observed for a sufficientlylong period (6 months or more) to allow estimation of the results.

Before and during the treatment, the patients were questioned withrespect to decrease of hairfall, decrease of oiliness and dandruff (ifpresent before treatment), improvement in the general condition of thehair, i.e. lustre, life, manageability and other subjective qualities,which had been impaired during the time period before treatment andregression of the thinning out often observed before treatment and inmany cases being the most important reason for seeking medical advice.

In some cases, the total assessment was made only on the basis of suchsubjective estimation by the patient, his or her family and thehairdresser. In most cases, to this information was added a directobservation of the amount of hair in samples taken at regular intervalsin connection with shampooing procedures, comparisons of photographstaken before and after the treatment, and differen- Females Males TotalObviously very good, well verified improvement. 16 2 18 Good, but lessobvious and less impressive improvement 21 22 43 Clearly positiv 37 2461 +1 Improvement observed, but not sufficiently clear or welldocumented to be classed as may get improved grade 12 7 19 after longerobservation 7 Improvement so far questionable, but some of these casesmay be classed as after longer observation 5 9 14 Negative or nearlynegative result, or possibly slight improvement 13 28 Doubtful ornegativ 5 On this basis, the percentage improved was 50%.

-(?) Stopped treatment too early to bring about a possible improvement.These may be classed as negative, but some 4 6 10 might have beenpositive after an adequate treatment period.

Totaltial counts of hair roots extracted during each of several visitsand studied according to a special method worked out for thisinvestigation. In contrast to the commonly used methods for hair rootstudies, this approach gives permanent preparations available forfurther studies when needed.

Side eifects: A boy of 1'8 observed swelling and slight tenderness ofthe mamillary area after three weeks treatment, disappearing again twoweeks after stopping the treatment. When this had happened twice,further experiments were abstained from.

With this exception, during the trial period of five years no systemicside eflfects have been observed, that could reasonably be considered tohave been caused by the treatment. Although many women have continuedtheir treatment over one or two years or even more, no more menstrualirregularities have been observed than might be expected to occurspontaneously during such a long observation period, particularly inpatient material with the present age distribution (several patientsapproaching the menopause).

It should be mentioned that two female patients observed increasedgrowth of facial (terminal) hair during treatment. This is a rathernatural consequence of the hormonal imbalance, that may induceandrogenetic hairfall and, in patients prone to this, also increasedgrowth of facial hairs. One of these patients maintains that herbeard-growing tendency was reduced by local (facial) application of 0Llotion.

Thus, the only systemic side eflFect observed was the above-mentionedreadily reversible gynecomastia.

Results of treatment: Several female patients have experienced anobvious improvement by way of diminution of hairfall, regression of thethinning out of the hair, and also reduction in the degree of oilyseborrhoea. They also report an improvement of the general structure andlayability of the hair. 'Many other female patients have experienced aless spectacular improvement in these respects, but still in theiropinion sufficiently important to make them very willing to continuetheir treatment over an extended period (several years).

In men, the results have necessarily been less spectacular. However, acontinuing hairfall has often decreased and a recently started thinningout of the hair has stopped in some cases. In several patients, theprocess appears to proceed more slowly under treatment. Also in On thebasis, the percentage improved was 61/132: 46.21%.

Except the cases, 122 patients have been studied. Including these cases,132 patients have been treated.

In addition to these patients, two female and 12 male patients havebegun treatment, but too late to have had time for a new visit whichwould allow sufficient observation for classification and gradingpurposes.

Treatment period: Some female patients, after having improved, can stoptreatment after about one year, and sometimes even less, probablybecause the hairfall-elicting hormonal imbalance Was only temporary.Most female patients, however, have continued their treatment for longerperiods. Several female patients have observed deterioration afterhaving tried to discontinue the treatment.

Male patients usually have to employ the treatment for a longer time toattain a clear improvement, and most of these will have to continue forextended periods.

It is to be understood that the invention is not to be limited to theexact details of operation or exact compounds or compositions shown anddescribed, as obvious modifications and equivalents will be apparent toone skilled in the art, and the invention is therefore to be limitedonly by the scope of the appended claims.

I claim:

1. A method of treating the scalp and hair of a human being sufferingfrom a non-irreversible condition involving hair fallout or thinning,which comprises administering topically to the area of the scalp subjectto the said condition an effective amount of estriol, in a topicalsolvent having a concentration of estriol of 0.02% to about 1% byweight, said solvent comprising water and a further solvent componentselected from the group consisting of a lower alcohol and acetone.

2. The method of claim 1, wherein ethyl alcohol is present as a furthersolvent component.

3. The method of claim 1, wherein isopropyl alcohol is present as afurther solvent component.

4. The method of claim 1, wherein both ethyl and isopropyl alcohol arepresent as further solvent components.

5. The method of claim 1, wherein the concentration of estriol is atleast 0.1% by weight.

6. The method of claim 1, wherein estriol is present in the saidcomposition in a concentration of approximately 0.1% by weight inaqueous ethyl alcohol solvent.

1 1 1 2 7. The method of claim 1, wherein the composition FOREIGNPATENTS is administered in an amount of about 20 ml. per week for aperiod of at least about twelve weeks. 61 12/1954 Great Bntam 424-319 8.The method of claim 1, wherein the composition is OTHER REFERENCESadministered in an amount of about ml. per week for a 5 period f atleast about Six months. 'Dodds, J. Soc. Cosmetic Chemists, vol. 16, N0.8, p.

i 9. The method of claim 1 wherein the composition is 434 relied on,July 1965. administered in an amount of about ml. per week for a periodof at least about twelve Weeks. ALBERT T. MEYERS, Primary ExaminerReferences Cited 10 V. C. CLARKE, Assistant Examiner UNITED STATESPATENTS US. Cl. X.R.

2,942,008 6/ 1960 Lubowe 424- X 424--Dig. 4, 70, 329

